Utilizing the apo E and LDL receptor knockout mouse models of atherosclerosis, this project proposes to identify new genes and pathways relevant to atherosclerosis susceptibility by applying the powerful techniques of mouse genetics and the emerging tools of the Genome Project. In addition, the experimental approach will heavily emphasize physiological studies of atherosclerosis related phenotypes both as an aid to gene identification and to better stand the function of apo E knockout, and a resistant strain, FVB/N apo E knockout, has revealed 3 atherosclerosis susceptibility loci not associated with lipoprotein phenotype. The specific aims are: 1) To identify the physiological and genetic basis of the knockout, strains. This will entail studies comparing parental strains for lesion progression, tissue contributions, macrophage metabolism, and gene expression. To identify the gene, secondary congenics will be made and the phenotype reconstructed. Secondary congenic will then be backcrossed and recombinants sought to narrow the genetic intervals. Ultimately, the response gene(s) will be identified through gene expression studies, sequencing, and creating transgenic or knockout mouse models. (2) To perform additional crosses between atherosclerosis susceptible and resistant apo E knockout and LDL receptor knockout mouse strains to reveal new genes that control atherosclerosis susceptibility. The first experiment will attempt to identify genes involved in lesion progression by crossing C57/Bl/6J apo E knockout and FVB/N apo E knockout mice with scoring of lesions in F2 mice on a chow diet at 40 weeks of age for lesion size, acellular lipid core size, collagen and smooth muscle cell content, and calcification. A second C57/Bl/6J apo E knockout mice) and FVB/N apo E knockout mice to identify a gender influenced atherosclerosis susceptibility gene. Finally, to create a FVB/N LDL receptor knockout and cross it with the C57Bl/6J LDL receptor knockout strain to identify genes that influence atherosclerosis susceptibility on the LDL receptor knockout but not the apo E knockout background. This project should identify new genes and pathways involved in atherosclerosis susceptibility.